The present invention relates to a new method of use of morphinans. The present invention relates to naltrexone or 17-cyclopropylmethyl-4,5α-epoxy-6-oxomorphinan-3,14-diol and nalmenfene or 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol or nalmefene, and their analogs, and pharmaceutical formulations thereof, and use thereof for prevention and treatment of NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease) and ASH (alcoholic steatohepatitis).
In PCT publication WO 03/097608, we have described a number of new medical uses of opioid and opioid-like compounds, including naltrexone and nalmefene. In PCT publication WO WO2006029167, we have described a number of new medical uses of 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol.
Recent advances in the research of neurodegenerative diseases of the central nervous system have revealed that the opioids may play a role in modulating the expression of inflammatory factors such as proinflammatory cytokines, free radicals and metabolites of arachidonic acid in microglia and in the mediation of immune-related neurodegeneration [Adv. Exp. Med. Biol. 1996, 402: 29-33; Mov. Disord. 1997; 12: 855-858] and neuropathic pain [Hutchinson M R, et al. Eur J Neurosci. 2008; 28:20-299]. A Chinese Patent application (CN102048733) claims the use of nalmefene for treatment of fatty liver due to the high fat diet via injection.
In this application, we disclose that nalmefene and naltrexone have demonstrated its efficacy in preventing and treating NAFLD, NASH, and ASH.
The present invention provides a method of the prevention of inflammatory hepatic injury in NAFLD and its progression to NASH.
The emerging epidemic of obesity and metabolic syndrome has contributed to the increased prevalence of NASH as what is now considered to be the leading cause of chronic liver disease in the Western world (Clark, J. M., et al., Nonalcoholic fatty liver disease. Gastroenterology, 2002; 122: 1649-1657). NASH affects 2 to 5 percent of Americans. An additional 10 to 20 percent of Americans have fat in their liver, but no inflammation or liver damage, a condition called “fatty liver.” Although having fat in the liver is not normal, by itself it probably causes little harm or permanent damage. If fat is suspected based on blood test results or scans of the liver, this condition is called nonalcoholic fatty liver disease (NAFLD). If a liver biopsy is performed in this case, it will show that some people have NASH while others have simple fatty liver. NASH or NAFLD resembles ASH (Alcoholic Steatohepatitis) or ALD (alcoholic liver disease) respectively but occurs in people who drink little or no alcohol [Ludwig, J., et al., Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc, 1980; 55: p. 434-438].
While the underlying causes of NASH remain unclear, several factors such as insulin resistance, release of toxic inflammatory proteins by fat cells (cytokines), and oxidative stress (deterioration of cells) inside liver cells may contribute to the morbidity of NASH (http://digestive.niddk.nih.gov/ddiseases/pubs/nash).
The exact mechanisms responsible for pathogenesis and progression of fatty liver disease are not entirely clear. Several studies have demonstrated that hepatic steatosis predisposes animals to greater injury in the presence of a subsequent stress such as endotoxemia. Since it is widely accepted that the transition from steatosis to steatohepatitis (NAFLD to NASH) is dependent upon a “second hit” such as oxidative stress or endotoxemia (Wanless I R, Shiota K. The pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. Semin Liver Dis. 2004; 24:99-106; Duvnjak M, et al. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol. 2007; 14; 13:4539-4550). It is now commonly accepted that the progression occurs as part of a “two hit” mechanism in which the first hit is lipid accumulation in the hepatocytes (steatosis) (Day C P, James O F. Steatohepatitis: a tale of two “hits” ? Gastroenterology 1998; 114: 842-845; Sanches SC et al. Nonalcoholic Steatohepatitis: A Search for Factual Animal Models. Biomed Res Int. 2015; 2015:574832). The second hit is presumed to be oxidative, endotoxemia or inflammatory stress. With repeated stresses the enhanced inflammatory response leads to hepatic injury and the onset of fibrosis. While the definitive treatment for fatty liver disease is the reversal of the steatosis through weight reduction and restoration of insulin sensitivity, this is not generally complete nor even practical in many cases.
Currently, there are no FDA-approved treatments for fatty liver disease and NASH or ASH. Experimental approaches under clinical evaluation in patients with NASH include antioxidants (for example, vitamin E), selenium, and betaine, as well as newer antidiabetic medications. The need for specific pharmacotherapy is now acknowledged by practitioners, the pharmaceutical industry, and regulators, and is greatly anticipated by patients. The result is a clear move away from products developed second hand for NASH (such as pioglitazone or metformin) or from generic, non-specific hepatoprotectants (such as pentoxifylline, ursodeoxycholic acid, or antioxidants) toward molecules developed and tested specifically for NASH that aim to correct one or several of the pathways of liver injury in this disease. The two most advanced molecules, obeticholic acid and elafibranor, have shown encouraging results on improving hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving liver fibrosis and elafibranor improving the glycemic and lipid profile [Ratziu V., Novel Pharmacotherapy Options for NASH. Dig Dis Sci. 2016 Mar. 22. (Epub ahead of print)].
Methionine-Choline-Deficient (MCD) diet mouse model is a well accepted model of NASH, as described above (cf. Rivera C A, et al. 2007; Sanches S C et al. Nonalcoholic Steatohepatitis: A Search for Factual Animal Models. Biomed Res Int. 2015; 2015:574832). Consequently the MCD diet mice have been widely used to test hepatoprotectant effects of compounds against NAFLD/NASH.
Nalmefene demonstrated efficacy in preventing inflammatory liver damage in the MCD rat model, followed by a second hit with LPS.
Alcoholic liver disease (ALD) Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide (Arsene et al. Hepatol Int. 2016; 10:538-552). The clinical and pathologic spectrum of ALD ranges from alcoholic fatty liver disease (alcoholic steatosis) to cirrhosis (Saberi et al. J Clin Transloat Hepotol. 2016; 4:113-122). ALD can be divided into alcohol-induced steatosis (microvesicular, macrovesicular), alcoholic steatohepatitis (ASH) and alcoholic cirrhosis. The pathology of ALD resembles that of NAFLD/NASH. ALD and NAFLD have a similar pathologic spectrum, and they have been described to coexist in the clinical setting (Toshikuni et al World J Gastroenterol 2014; 20:8393-8406; Brunt and Tiniakos. World J Gastroenterol 2010; 16:5286-5296). Acute and chronic ingestion of alcohol lead to a strong elevation of portal and systemic levels of endotoxin in animal models and humans (Porlesok et al. J Hepotol 2000; 32:742-747). Endotoxin is a crucial mediator of liver injury in alcoholic liver disease as demonstrated by the significant reduction of alcoholic liver injury following elimination of the Gram-negative microbiota by antibiotics, and the sensitization to LPS-induced liver injury following long-term ethanol exposure. The elevation of endotoxin appears to be predominantly caused by two mechanisms. First, alcohol consumption leads to changes in the intestinal microbiota with bacterial overgrowth in the upper gastrointestinal tract (Hauge et al. Digestion 1997; 58:591-595). Second, alcohol ingestion is known to disrupt the intestinal epithelial barrier causing enhanced permeability thus allowing increased levels of LPS to enter the portal circulation (Bjornason et al. Lancet 1984; 1:179-182). Kupffer cells have been established as a crucial cellular target of LPS in ethanol-induced liver injury (Adachi et al. Hepatology 1994; 20:453-460). Experimental models of ALD have revealed that translocation of bacterial products across the intestinal barrier to the portal circulation triggers inflammatory responses in the liver and contributes to steatohepatitis. The most effective measure to manage ASH is alcohol abstinence by alcoholic patients. Steroids have some short term benefit in treatment of severe ASH, but long term effect is unclear due to numerous side effects. Consequently, there is an urgent need to focus discovery efforts on effective therapeutic interventions for ASH.